Coccidioidomycosis (Valley Fever) is a systemic fungal infection which sickens 50,000 Americans annually, resulting in hundreds of millions of dollars in economic loss. Currently available treatments only inhibit the fungus so that if treatment is stopped disease often recurs. Nikkomycin Z (NikZ) is a first-in-class antifungal drug that inhibits a part of the fungal cell wall. In experimental infections, NikZ has eradicated Valle Fever, suggesting that in humans it might produce cures. The University of Arizona has assumed the responsibility for developing this potentially very important advance in public health because at present no pharmaceutical company has been willing to do so. A small business, Valley Fever Solutions (VFS), was created to assist the University of Arizona in this development effort. The University of Arizona conducted a safety study in humans which justifies further studies and VFS has improved the means of manufacturing NikZ. These advances allow the production of new supplies of NikZ and the resumption of clinical trials. In this proposal, VFS will obtain NikZ, freshly made under contract to the National Institutes of Health, for a clinical study in humans. Persons with newly acquired Valley Fever most commonly suffer many weeks to many months of pneumonia illness before eventually improving. This study will enroll 48 such patients to receive either NikZ given by mouth for four weeks and compare their improvement to other subjects who will receive a placebo treatment. This study will allow us to estimate whether early treatment is likely to reduce the overall impact of Valley Fever infections for the most commonly encountered illness. If this study is successful, it will pave the way for a larger definitive study to more precisely determine the benefit of treatment of early Valley Fever infections. Future studies could extend the use of NikZ to increasingly serious and complicated infections.